Recurrent herpes simplex keratitis is a major cause of morbidity and visual loss in man. At the present time no reliable means of preventing recurrent disease exists. Between episodes herpes virus appears to reside in some form in the nuclei of the trigeminal ganglion. Clinically, triggers such as febrile illness, emotional stress, sunlight, and trauma have been associated with recurrence of corneal disease. All of these are systems in which cellular cyclic AMP is elevated, either through synthesis of prostaglandins or epinephrine release. The proposed research will attempt to elucidate the mechanism of herpes recurrences by study of cyclic AMP stimulators and inhibitors in an animal model. Rabbits will be infected with herpes simplex virus by topical corneal instillation. These rabbits will develop acute corneal disease which will spontaneously heal. The animals will then recurrently shed virus into the conjunctival cul-de-sac and at times also develop corneal ulcerative disease. The proposed experiments will attempt to alter the frequency of current diseases through both local and systemic instillation of various inhibitors and stimulators of inflammation. In addition, later studies will use the same agents by stereotactic instillation in the region of the trigeminal ganglion. The following agents will be investigated in this model: indomethacin, a prostaglandin synthetase inhibitor both topically and systemically; epinenephrine, topically and systemically; arachidonic acid, a prostaglandin precursor topically and systemically; and dibutyryl cyclic AMP topically. Electron microscopic studies will also be carried out in animals stimulated by stereotactic peri-ganglionic drug instillation to determine the anatomic pattern of virus release. Hopefully a better understanding of the mechanism of recurrences will lead to clinical therapy to prevent devastating corneal disease.